Autotaxin (ATX) is an autocrine motility factor that promotes cancer cell invasion, cell migration and angiogenesis. ATX, originally discovered as a nucleotide phosphodiesterase, is known now to be responsible for the lysophospholipid-preferring phospholipase D activity in plasma. As such, it catalyzes the production of lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). ATX is thus an attractive drug target; small molecular inhibitors might be efficacious in slowing the spread of cancers. With this study we have generated a series of beta-keto and beta-hydroxy phosphonate derivatives of LPA, some of which are potent ATX inhibitors.
The autocrine motility factor autotaxin (ATX) was originally isolated from melanoma cell supernatants as a 125-kD glycoprotein that stimulated tumor cell motility. In vivo experiments documented that forced expression of ATX augments tumor cell invasion and metastasis. Further, ATX promotes angiogenesis and may act in concert with other angiogenic factors to facilitate new blood vessel formation. These biological properties require enzymatic activity.
ATX belongs to the nucleotide pyrophosphatase and phosphodiesterase (NPP) family of enzymes, which hydrolyze phosphodiester and diphosphate bonds, typically found in ATP and ADP. Interest in ATX was stimulated by the identification of this enzyme as the long elusive plasma lysophospholipase D activity, which is responsible for the cleavage of choline group of lysophosphatidylcholine (LPC) to form lysophosphatidic acid (LPA). This is a major pathway of biosynthesis of LPA in plasma. LPA is an intercellular lipid mediator that influences many biochemical processes including cell proliferation, smooth muscle contraction, platelet aggregation and apoptosis. For example, LPA is the “ovarian cancer activating factor” in ascitic fluid characteristic of ovarian cancer patients. Elevated levels of LPA are present both at early and late stages in ovarian cancer and may play a role in tumor cell proliferation and invasion. LPA mediates its effects through the activation of G protein-coupled receptors (GPCR). Thus, great efforts have been made on the study of LPA receptor antagonists and agonists due to their therapeutic potential. In aggregate, these data suggest that ATX is an attractive pharmacological target; blockage of LPA production via ATX inhibition by small molecules could be a useful anticancer chemotherapy. A limited number of ATX inhibitors that are LPA analogs are known.
Currently, there is a need for novel, potent, and selective compounds that inhibit ATX. These compounds can be useful for preventing or treating cancer. The present invention satisfies these needs.